WO2011157793A1 - Dérivés de 1,3‑dihydro-benzoimidazol-2-ylidène-amine à substitution pipéridinyle - Google Patents

Dérivés de 1,3‑dihydro-benzoimidazol-2-ylidène-amine à substitution pipéridinyle Download PDF

Info

Publication number
WO2011157793A1
WO2011157793A1 PCT/EP2011/060032 EP2011060032W WO2011157793A1 WO 2011157793 A1 WO2011157793 A1 WO 2011157793A1 EP 2011060032 W EP2011060032 W EP 2011060032W WO 2011157793 A1 WO2011157793 A1 WO 2011157793A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
alkyl
compound
mmol
halo
Prior art date
Application number
PCT/EP2011/060032
Other languages
English (en)
Inventor
Frederic Berst
Pascal Furet
Andreas Marzinzik
Frédéric STAUFFER
Original Assignee
Novartis Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis Ag filed Critical Novartis Ag
Priority to CN201180029739XA priority Critical patent/CN102947275A/zh
Priority to EP11725116.5A priority patent/EP2582681A1/fr
Priority to US13/704,380 priority patent/US20130085161A1/en
Priority to JP2013514720A priority patent/JP2013532149A/ja
Publication of WO2011157793A1 publication Critical patent/WO2011157793A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the invention relates to new derivatives of 1 H-benzo[d]imidazol-2(3H)-imines; processes for the preparation of such derivatives; pharmaceutical compositions comprising such derivatives optionally in combination with one or more other pharmaceutically active compounds; such derivatives optionally in combination with one or more other pharmaceutically active compounds as a medicament; such derivatives optionally in combination with one or more other pharmaceutically active compounds for the treatment of a proliferative disease, such as a tumour disease (also including a method for the treatment of such diseases in mammals, especially in humans); and the use of such derivatives for the preparation of a pharmaceutical composition (medicament) for the treatment of a proliferative disease, such as a tumour.
  • a proliferative disease such as a tumour disease
  • a pharmaceutical composition mediumcament
  • IGF-1 Insulin-like growth factor
  • IGF-1 R IGF-1 receptor
  • WO 2005/097800 discloses certain 6,6-bicyclic ring substituted heterobicyclic derivatives having therapeutic activity as IGF-1 R inhibitors.
  • WO 2005/037836 discloses certain imidazopyrazine derivatives having therapeutic activity as IGF-1 R inhibitors.
  • WO2006/074991 discloses certain 1 H-benzo[d]imidazol-2(3H)-imines having therapeutic activity as modulators of the SK-channels.
  • the present invention relates to new derivatives of 1 H-benzo[d]imidazol-2(3H)-imines of formula (I)
  • the invention also relates to processes for the preparation of such derivatives; pharmaceutical compositions comprising such derivatives optionally in combination with one or more other pharmaceutically active compounds; such derivatives optionally in combination with one or more other pharmaceutically active compounds as a medicament; such derivatives optionally in combination with one or more other pharmaceutically active compounds for the treatment of a proliferative disease, such as a tumour disease (also including a method for the treatment of such diseases in mammals, especially in humans); and the use of such derivatives for the preparation of a pharmaceutical composition (medicament) for the treatment of a proliferative disease, such as a tumour.
  • a proliferative disease such as a tumour disease
  • a pharmaceutical composition mediumcament
  • n 0, 1 , 2, 3 or 4;
  • n 0, 1 , 2, 3 or 4;
  • q 0, 1 , 2 or 3;
  • X represents a group
  • a 1 represents N, CH or CR 5 ;
  • a 2 represents N, CH or CR 5 ;
  • R 1 represents halogen, Ci -7 alkyl, Ci -7 alkyoxy, halo-Ci -7 alkyl or halo-Ci -7 alkyoxy; and/or R 1 represents, provided two substituents R 1 are in vicinal position, together with the carbon atoms to which they are attached a cyclic moiety, said moiety (a) being saturated or partly saturated, (b) contains 5 - 8 ring forming atoms, (c) contains 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-2 sulfur atoms, and (d) is unsubstituted or substituted, the substituents being selected from the group consisting of halogen,
  • R 2 represents hydrogen, halogen, C 1-7 alkyl or halo-C 1-7 alkyl
  • R 3 represents hydrogen, Ci -7 alkyl, halo-Ci -7 alkyl, Ci -7 alkyl-carbonyl, halo-Ci -7 alkyl- carbonyl, Ci -7 alkoxy-carbonyl, or halo-Ci -7 alkoxy-carbonyl;
  • R 4 represents halogen, Ci -7 alkyl, Ci -7 alkoxy, halo-Ci -7 alkyl or halo-Ci -7 alkoxy;
  • R 5 represents a substituent different from hydrogen, said substituent (a) having 1 -50 atoms selected from the group consisting of hydrogen, carbon, halogen and hetero atoms and (b) being bound via a single bond;
  • R 6 represents hydrogen, hydroxy, halogen, Ci -7 alkyl, Ci -7 alkyoxy, halo-Ci -7 alkyl or halo-C 1-7 alkyoxy.
  • the compounds of formula (I) are potent inhibitors of the tyrosine kinase activity of the Insulin-like growth factor I receptor (IGF-IR) and inhibit IGF-IR- dependent cell proliferation.
  • IGF-IR Insulin-like growth factor I receptor
  • the pesence of the substituents of the scaffold as defined below is considered important for the efficacy, tolerability and/or the selectivty of the compounds of the present invention as IGF-IR tyrosine kinase inhibitors and their potential to inhibit IGF-IR-dependent cell proliferation.
  • the compounds of the present invention are therefore potentially useful in the treatment of a wide range of disorders, particularly the treatment of proliferative diseases.
  • the compounds of formula (I) therefore permit, for example, a therapeutic approach, especially for diseases in the treatment of which, and also for the prevention of which, an inhibition of the IGF-IR tyrosine kinase and/or of the IGF-IR-dependent cell proliferation shows beneficial effects.
  • diseases include proliferative diseases, such as tumours, like for example breast, renal, prostate, colorectal, thyroid, ovarian, pancreas, neuronal, lung, uterine and gastro-intestinal tumours as well as osteosarcomas and melanomas.
  • Compounds of the invention show improved efficacy, tolerability and/or selectivity when compared to known IGF-1 R inhibitors. Without being bound to theory, it is believed that several factors contribute to the improvements in efficacy and tolerability, for example increased metabolic stability and the reduced formation of multiple kinase-active metabolites. Although known compounds have been shown to produce desirable effects in in-vivo models through the inhibition of IGF-1 receptor activity, they have been found to undergo extensive metabolism. This not only limits the pharmacokinetic profile of such derivatives, but also generates metabolites, which show multiple potent kinase activities.
  • the term “compounds of the present invention” refers to compounds of formula (I) and subformulae thereof (add other additional genus structures as necessary), prodrugs thereof, salts of the compound and/or prodrugs, hydrates or sol- vates of the compounds, salts and/or prodrugs, as well as all stereoisomers (including diastereoisomers and enantiomers), tautomers and isotopically labeled compounds (including deuterium substitutions), as well as inherently formed moieties (e.g., polymorphs, solvates and/or hydrates).
  • the term “isomers” refers to different compounds that have the same molecular formula but differ in arrangement and configuration of the atoms.
  • an optical isomer or "a stereoisomer” refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the invention includes enantiomers, diaste- reomers or racemates of the compound. "Enantiomers” are a pair of stereoisomers that are non- superimposable mirror images of each other. A 1 :1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to designate a racemic mixture where appropriate.
  • Diastereoisomers are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • the absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S.
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain of the compounds described herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures.
  • Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubsti- tuted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.
  • any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (/?)-, (S)- or ⁇ R,S)- configuration.
  • each asymmetric atom has at least 50 % enantiomeric excess, at least 60 % enantiomeric excess, at least 70 % enantiomeric excess, at least 80 % enantiomeric excess, at least 90 % enantiomeric excess, at least 95 % enantiomeric excess, or at least 99 % ee in the (R)- or (S)- configuration.
  • Substituents at atoms with unsaturated bonds may be present in cis- (Z)- or trans- (£)- form.
  • R 3 may be present in cis-form, trans-form or mixtures thereof.
  • R 6 may be present in cis-form, trans-form or mixtures thereof, whereby cis / trans relates to the relative position of R 6 in relation to the core benzimidazole-moiety.
  • a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof. Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
  • any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-0,0'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid.
  • Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
  • HPLC high pressure liquid chromatography
  • salt refers to an acid addition or base addition salt of a compound of the invention.
  • Salts include in particular “pharmaceutical acceptable salts”.
  • pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable.
  • the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfornate, chloride/hydrochloride, chlor- theophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicoti- nate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propio- nic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesul- fonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like.
  • Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods.
  • such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • use of nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable.
  • Compounds of the present invention are either obtained in the free form, as a salt thereof, or as prodrug derivatives thereof.
  • the compounds of the present invention may also form internal salts, e.g., zwitterionic molecules.
  • the present invention also provides pro-drugs of the compounds of the present invention that converts in vivo to the compounds of the present invention.
  • a pro-drug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a subject.
  • the suitability and techniques involved in making and using pro-drugs are well known by those skilled in the art.
  • Prodrugs can be conceptually divided into two non-exclusive categories, bioprecursor prodrugs and carri- er prodrugs. See The Practice of Medicinal Chemistry, Ch. 31 -32 (Ed. Wermuth, Academic Press, San Diego, Calif., 2001 ).
  • bioprecursor prodrugs are compounds, which are inactive or have low activity compared to the corresponding active drug compound that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity.
  • Carrier prodrugs are drug compounds that contain a transport moiety, e.g., that improve uptake and/or localized delivery to a site(s) of action. Desirably for such a carrier prodrug, the linkage between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, and any released transport moiety is acceptably non-toxic.
  • Carrier prodrugs can, for example, be used to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effects, increased site-specificity, decreased toxicity and adverse reactions, and/or improvement in drug formulation (e.g., stability, water solubility, suppression of an undesirable organoleptic or physiochemical property).
  • lipophilicity can be increased by esterification of (a) hydroxyl groups with lipophilic carboxylic acids (e.g., a carboxylic acid having at least one lipophilic moiety), or (b) carboxylic acid groups with lipophilic alcohols (e.g., an alcohol having at least one lipophilic moiety, for example aliphatic alcohols).
  • lipophilic carboxylic acids e.g., a carboxylic acid having at least one lipophilic moiety
  • lipophilic alcohols e.g., an alcohol having at least one lipophilic moiety, for example aliphatic alcohols
  • prodrugs are, e.g., esters of free carboxylic acids and S-acyl derivatives of thiols and O-acyl derivatives of alcohols or phenols, wherein acyl has a meaning as defined herein.
  • Suitable prodrugs are often pharmaceutically acceptable ester derivatives convertible by solvolysis under physiological conditions to the parent carboxylic acid, e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkyl esters, such as the co-(amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters, the a-(lower alkanoyloxy, lower alkox- ycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxyme- thyl
  • amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)).
  • drugs containing an acidic NH group such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.
  • EP 039,051 (Sloan and Little) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
  • the compounds of the present invention can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • the compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms.
  • solvate refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules.
  • solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like.
  • hydrate refers to the complex where the solvent molecule is water.
  • the compounds of the present invention, including salts, hydrates and solvates thereof may inherently or by design form polymorphs.
  • co-crystals may be capable of forming co-crystals with suitable co-crystal formers.
  • co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) with the co- crystal former under crystallization conditions and isolating co-crystals thereby formed.
  • Suitable co-crystal formers include those described in WO 2004/078163.
  • the invention further provides co-crystals comprising a compound of formula (I).
  • any formula given herein is also intended to represent unlabeled forms as well as iso- topically labeled forms of the compounds.
  • Isotopically labeled compounds have struc- tures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F 31 P, 32 P, 35 S, 36 CI, 125 l respectively.
  • the invention includes various isotopically la- beled compounds as defined herein, for example those into which radioactive isotopes, such as 3 H, 13 C, and 14 C , are present.
  • Such isotopically labelled compounds are useful in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single- photon emission computed tomography (SPECT) including drug or substrate tissue dis- tribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single- photon emission computed tomography
  • an 18 F or labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
  • substitution with heavier isotopes, particularly deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index.
  • deuterium in this context is regarded as a substituent of a compound of the formula (I).
  • the concentration of such a heavier isotope, specifical- ly deuterium may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each des- ignated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopi- cally-labeled reagents in place of the non-labeled reagent previously employed.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, de- acetone, de-DMSO.
  • the term "a,” “an,” “the” and similar terms used in the context of the present invention are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.
  • the selection of a particular moiety from a list of possible species for a specified variable is not intended to define the moiety for the variable appearing elsewhere.
  • the choice of the species from a specified list is independent of the choice of the species for the same variable elsewhere in the formula (where one or more up to all more general expressions in embodiments characterized as preferred above or below can be replaced with a more specific definition, thus leading to a more preferred embodiment of the invention, respectively).
  • Carbon containing groups, moieties or molecules contain 1 to 12, preferably 1 to 7, more preferably 1 to 4, most preferably 1 or 2, carbon atoms. Any non-cyclic carbon containing group or moiety with more than 1 carbon atom is straight-chain or branched.
  • the prefix "lower” denotes a radical having 1 to 7, preferably 1 to 4 carbon atoms, the radicals in question being either unbranched or branched with single or multiple branching.
  • halogen denotes fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine.
  • Halogen-substituted groups and moieties, such as alkyl substituted by halogen (haloalkyl) can be mono-, poly- or per-halogenated.
  • hetero atoms denotes atoms other than Carbon and Hydrogen, preferably nitrogen (N), oxygen (O) or sulfur (S), in particular nitrogen or oxygen.
  • alkyl refers to a fully saturated branched or unbranched hy- drocarbon moiety having up to 20 carbon atoms. Unless otherwise provided, alkyl refers to hydrocarbon moieties having 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, / ' so-propyl, n-butyl, sec-butyl, / ' so-butyl, ferf-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
  • a substituted alkyl is an alkyl group containing one or more, such as one, two or three substituents as defined herein.
  • alkylene refers to divalent alkyl group as defined herein above having 1 to 20 carbon atoms. It comprises 1 to 20 carbon atoms, Unless otherwise provided, alkylene refers to moieties having 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms.
  • alky- lene examples include, but are not limited to, methylene, ethylene, n-propylene, /so-propylene, n- butylene, sec-butylene, / ' so-butylene, ferf-butylene, n-pentylene, isopentylene, neopenty- lene, n-hexylene, 3-methylhexylene, 2,2- dimethylpentylene, 2,3-dimethylpentylene, n- heptylene, n-octylene, n-nonylene, n-decylene and the like.
  • a substituted alkylene is an alkylene group containing one or more, such as one, two or three substituents as defined herein.
  • haloalkyl refers to an alkyl as defined herein, which is substituted by one or more halo groups as defined herein.
  • the haloalkyl can be monohaloal- kyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl.
  • a monohaloalkyl can have one iodo, bromo, chloro or fluoro within the alkyl group.
  • Dihaloalky and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl.
  • the polyhaloalkyl contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups.
  • Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluo- ropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichlo- roethyl and dichloropropyl.
  • a perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halo atoms.
  • alkoxy refers to alkyl-O-, wherein alkyl is defined herein above.
  • alkoxy examples include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, ferf-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like.
  • alkoxy groups typically have 1 -16, 1-10, 1-7, more preferably 1-4 carbon atoms.
  • a substituted alkoxy is an alkoxy group containing one or more, such as one, two or three substituents as defined herein; preferably halo.
  • alkyl part of other groups like “alkylaminocrabonyl”, “alkoxyalkyl”, “alkox- ycarbonyl”, “alkoxy-carbonylalkyl”, “alkylsulfonyl”, “alkylsulfoxyl”, “alkylamino”, “haloalkyl” shall have the same meaning as described in the above-mentioned definition of “alkyl”.
  • cycloalkyi refers to saturated or unsaturated monocyclic, bi- cyclic, tricyclic or spirocyclic hydrocarbon groups of 3-12 carbon atoms. Unless otherwise provided, cycloalkyi refers to cyclic hydrocarbon groups having between 3 and 9 ring carbon atoms or between 3 and 7 ring carbon atoms.
  • a substituted cycloalkyi is a cycloylkyl group containing one or more substituents as defined herein.
  • a substituted cycloalkyi is a cycloalkyi group substituted by one, or two, or three, or more substituents independently selected from the group consisting of alkyl, halo, oxo, hy- droxy, alkoxy, alkyl-C(O)-, acylamino, carbamoyl, alkyl-NH-, (alkyl)2N-, thiol, alkyl-S-, ni- tro, cyano, carboxy, alkyl-O-C(O)-, sulfonyl, sulfonamido, sulfamoyl, and heterocyclyl.
  • Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like.
  • Exem- plary bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaph- thyl, decahydronaphthyl, bicyclo[2.1 .1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1 ]heptenyl, 6,6-dimethylbicyclo[3.1 .1 ]heptyl, 2,6,6-trimethylbicyclo[3.1 .1 ]heptyl, bicyclo[2.2.2]octyl and the like.
  • Exemplary tricyclic hydrocarbon groups include adamantyl and the like.
  • each cycloalkyl part of other groups like “cycloalkyloxy”, “cycloalkoxyalkyl”, “cycloalkoxycarbonyl”, “cycloalkoxy-carbonylalkyl”, “cycloalkylsulfonyl”, “halocycloalkyl” shall have the same meaning as described in the above-mentioned definition of "alkyl”.
  • aryl refers to an aromatic hydrocarbon group having 6-20 carbon atoms in the ring portion. Typically, aryl is monocyclic, bicyclic or tricyclic aryl having 6-20 carbon atoms. Furthermore, the term “aryl” as used herein, refers to an aromatic substituent which can be a single aromatic ring, or multiple aromatic rings that are fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl. A substituted aryl is an aryl group containing one or more substituents as defined herein.
  • a substituted aryl is an aryl group substituted by 1 -5 (such as one, or two, or three) substituents independently selected from the group consisting of alkyl, haloalkyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(0)-0-, aryloxy, heteroaryloxy-, amino, thiol, alkylthio, arylthio-, nitro, cyano, carboxy, alkyl-O-C(O)-, carbamoyl, alkyl-S(O)-, sulfonyl, sulfonamido, aryl and heterocyclyl.
  • 1 -5 such as one, or two, or three substituents independently selected from the group consisting of alkyl, haloalkyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(0)-0-, aryloxy, heteroaryloxy
  • heterocyclyl refers to a heterocyclic radical that saturated or partially saturated and is preferably a monocyclic or a polycyclic ring (in case of a poly- cyclic ring particularly a bicyclic, tricyclic or spirocyclic ring); and has 3 to 24, more preferably 4 to 16, most preferably 5 to 10 and most preferably 5 or 6 ring atoms; wherein one or more, preferably one to four, especially one or two ring atoms are a heteroatom (the remaining ring atoms therefore being carbon).
  • the bonding ring i.e. the ring connecting to the molecule
  • the bonding ring preferably has 4 to 12, especially 5 to 7 ring atoms.
  • the term heterocyclyl excludes heteroaryl.
  • the heterocyclic group can be attached at a heteroa- torn or a carbon atom.
  • the heterocyclyl can include fused or bridged rings as well as spirocyclic rings.
  • heterocycles include tetrahydrofuran (THF), dihydrofuran, 1 , 4-dioxane, morpholine, 1 ,4-dithiane, piperazine, piperidine, 1 ,3-dioxolane, imidazoli- dine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, di- thiolane, 1 ,3-dioxane, 1 ,3-dithiane, oxathiane, thiomorpholine, and the like.
  • a substituted heterocyclyl is a heterocyclyl group containing one or more substituents as defined herein.
  • heterocyclyl part of other groups like “heterocyclyloxy”, “heterocyclylox- yalkyl”, “heterocyclyloxycarbonyl” shall have the same meaning as described in the above-mentioned definition of “heterocyclyl”.
  • heteroaryl refers to a 5-14 membered monocyclic- or bicyclic- or tricyclic-aromatic ring system, having 1 to 8 heteroatoms.
  • the heteroaryl is a 5-10 membered ring system (e.g., 5-7 membered monocycle or an 8-10 memberred bi- cycle) or a 5-7 membered ring system.
  • Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5- pyrazolyl, 2-, 4-, or 5- thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1 ,2,4- triazolyl, 4- or 5-1 ,2, 3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or
  • heteroaryl also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8- indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7- isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8- purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinoliyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinoliyl, 1 -, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, or 6- naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazoliny
  • 6- or 7-pteridinyl, 1 -, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4aH carbazolyl, 1 -, 2-, 3-, 4-, 5-, 6-, 7-, or 8-carbzaolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10- phenanthridinyl, 1 - , 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1 -, 2-, 4-, 5-, 6-, 7-, 8-, or 9- perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl, 1-, 2- , 3-, 4-, 6-, 7-, 8-, or 9- phenazinyl, 1 -, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phen
  • Typical fused heteroary groups include, but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8- quinolinyl, 1 -, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5- , 6-, or 7-benzo[b]thienyl, 2-, 4-, 5- , 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7- benzimidazolyl, and 2-, 4-, 5-, 6-, or 7-benzothiazolyl.
  • a substituted heteroaryl is a he- teroyryl group containing one or more substituents as defined herein.
  • heteroaryl part of other groups like “heteroaryloxy”, “heteroaryloxyalkyl”, “heteroaryloxycarbonyl” shall have the same meaning as described in the above- mentioned definition of “heteroaryl”.
  • substituted or " a substituent different from hydrogen” refers to a moity that is substituted by one or more, typically 1 , 2, 3 or 4, covalently bound suitable non-hydrogen substituents; said substituent containing 1 - 50 atoms selected from the group consisting of hydrogen, carbon, halogen and hetero atoms.
  • non-hydrogen substituents are each independently selected from the group consisting of: (a) halo, nitro, cyano;
  • each cycloalkyl, aryl, heterocyclyl, heteroaryl may be substituted with halogen, hydroxy, alkyl, alkoxy, haloalkyl, haloakloxy, cycloalkyl, amino, alkylamino, dialkylamino alkyl-C(0)-NH-, alkyl-NH-C(O)-, as defined herein and wherein each alkyl may be substi- tuted with halogen, hydroxy, alkoxy, haloalkyl, haloakloxy, cycloalkyl, amino, alkylamino, dialkylamino alkyl-C(0)-NH-, alkyl-NH-C(O)-, as defined herein and wherein each sulfonyl, sulfoxy, sulfamoyl, sulfonamido may be substituted with alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl.
  • the invention relates to a compound of the formula (I), wherein the substituents are as defined herein.
  • the invention further relates to pharmaceutically acceptable prodrugs of a compound of formula (I).
  • the present invention also relates to pro-drugs of a compound of formula (I) as defined herein that convert in vivo to the compound of formula (I) as such.
  • the invention further relates to pharmaceutically acceptable metabolites of a compound of formula (I).
  • the invention provides a compound of the formula (I), or a salt thereof, depicted by formula (1-1 )
  • the invention provides a compound of the formula (I), or a salt thereof, depicted by formula (I-2)
  • the invention provides a compound of the formula (I), or a salt thereof, depicted by formula (I-3)
  • the invention provides a compound of the formula (I), or a salt thereof, depicted by formula (I-4)
  • the invention provides a compound of the formula (I), or a salt thereof, depicted by formula (I-5)
  • the invention provides a compound of the formula (I), or a salt hereof, depicted by formula (I-6)
  • the invention provides a compound of the formula (I), or a salt thereof, depicted by formula (I-7)
  • the invention provides a compound of the formula (I), or a salt thereof, depicted by formula (I-8)
  • the invention provides a compound of the formula (I), or a salt thereof, depicted by formula (I-9)
  • the invention provides a compound of the formula (I), or a salt thereof, depicted by formula (1-10)
  • n 0, 1 , 2 or 3; particularly 1 or 2.
  • n 0, or 1 ; particularly 0.
  • q represents 0, 1 or 2; particularly 1 or 2.
  • q represents 2, the substituents R 5 being located in the 2- and
  • q represents 1 , the substituent R 5 being located in the 2- or 3- position.
  • R 1 represents halogen; particularly fluoro or chloro.
  • R 1 represents, together with the phenyl ring, an unsubstituted or substituted indolyl, isoindolyl, indazolyl, benzimidazolyl, benztriazolyl, chinolinyl, isochinnolinyl, cinnolinyl, phtalazinyl, chazolinyl, chinoxalinyl, naphtalenyl, tetrahydro- naphtalenyl, indenyl, dihydro-indenyl, the substituents being selected from the group consisting of halogen.
  • R 1 represents, together with the phenyl ring, an unsubstituted or substituted indolyl, benzimidazolyl, benztriazolyl, the substituents being selected from the group consisting of fluoro and chloro.
  • R 2 represents hydrogen or Ci -7 alkyl; particularly hydrogen.
  • R 3 represents hydrogen, Ci -7 alkyl-carbonyl or Ci -7 alkyloxy- carbonyl; particularly hydrogen or acetyl.
  • R represents halogen; particularly fluoro.
  • R 5 represents a group -X " -R 5" wherein
  • X " represents either a single bond or a linker selected from the group consisting of 1 -7 alkyl
  • R 5" represents hydroxy, halo, cyano, carboxy, aminocarbonyl (C0NH2), amino, or optionally substituted Ci -7 alkyl, optionally substituted C 3- i 2 cycloalkyl, optionally substituted C 6-2 oaryl, optionally substituted heterocyclyl having 3-24 ring atoms, optionally substituted heteroaryl having 5-14 ring atoms, the optional substituents being selected from the group consisting of hydroxy, halo, cyano, carboxy, aminocarbonyl , amino, C-i. 7 alkylamino, di (Ci -7 alkyl)amino, Ci -7 alkyl, Ci -7 alkyloxy.
  • R 5 represents a group -X " -R 5" wherein
  • R 5" represents represents hydroxy, halo, cyano, carboxy, aminocarbonyl (CONH 2 ), amino, Ci -7 alkyl or substituted Ci -7 alkyl, the substituents being selected from the group consisting of hydroxy, halo, amino, Ci -7 alkylamino, Ci -7 alkyloxy.
  • R 5 represents a group -X " -R 5" wherein
  • X " represents a linker selected from the group consisting of
  • R 5" represents optionally substituted Ci -4 alkyl, optionally substituted C 3 - 9 cycloalkyl, optionally substituted C 6 -ioaryl, optionally substituted heterocyclyl having 4-16 ring atoms, optionally substituted heteroaryl having 5-10 ring atoms, the optional substituents being selected from the group consisting of hydroxy, halo, cyano, carboxy, amino-carbonyl , amino, Ci -7 alkylamino, di (Ci -7 alkyl)amino, Ci -7 alkyl.
  • R 5 represents methyl, methoxy, acetylamino, chloro, cyano, trifluoromethyl.
  • R 6 represents hydrogen, hydroxy, Ci -7 alkyoxy or halo-Ci -7 alkyoxy; particularly hydrogen or hydroxy.
  • a 1 represents N or CR 5 ; particularly CR 5 .
  • a 2 represents CH or CR 5 ; particularly CH.
  • the present invention relates to a compound of formula (I) mentioned in the Examples below, or a salt, especially a pharmaceutically acceptable salt, thereof.
  • the invention relates in a second aspect to the manufacture of a compound of formula (I).
  • the compounds of formula (I) or salts thereof are prepared in accordance with processes known per se (see references cited above), though not previously described for the manufacture of the compounds of the formula (I).
  • the inveniton relates to a process for manufacturing a compound of formula (I) wherein R 3 represents hydrogen, said method comprising the step of reacting a compound of formula (II)
  • Lg 1 represents a suitable leaving group, such as halogen (e.g. fluoro or chloro); optionally in the presence of one or more reaction aids, such as an organic or inorganic base (e.g. NEt3, diisopropylethylamine, Na 2 C0 3 , Cs 2 C0 3 , K 2 C0 3 ); optionally in the presence of one or more diluents, particular polar solvents (e.g. DMF, THF, MeCN, NMP).
  • This type of reaction is also known as nucleophilic aromatic substitution, typical reaction conditions are known in the field and may applied to the present process.
  • the compounds of formula (I) obtained by this method contain a nitro group R 5 and optionally one or more other substituents R 5 . Such nitro group may be removed or converted into other groups according to standard methods in one or more subsequent reaction steps.
  • the invention relates to a process for manufacturing a compound of formula (I) wherein R 3 represents hydrogen, said method comprising the step of reacting a compound of formula (IX)
  • Lg 2 represents a suitable leaving group, such halogen (e.g.bromo, chloro, iodo); optionally in the presence of one or more reaction aids, such as a base (e.g. Na 2 C0 3 ) or an inorganic salt (e.g. Kl); optionally in the presence of one or more diluents, particularly polar solvents (e.g. water, MeCN).
  • reaction aids such as a base (e.g. Na 2 C0 3 ) or an inorganic salt (e.g. Kl); optionally in the presence of one or more diluents, particularly polar solvents (e.g. water, MeCN).
  • This type of reaction is also known as alkylation reaction, typical reaction conditions are known in the field and may be applied to the present process.
  • the compounds of formula (I) obtained by this method may contain a nitro group R 5 and optionally one or more other substituents R 5 . Such nitro group may be removed or converted into other groups
  • the invention relates to a process for manufacturing a compound of formula (I) wherein R 3 represents a substituent as defined herein except hydrogen, said method comprising the step of reacting a compound of formula (XIII)
  • R 3 represents as substituent as defined herein for R 3 except hydrogen and Lg 5 represents a suitable leaving group, such as halogen (e.g. chloro, fluoro, bromo); optionally in the presence of one or more reaction aids, such as an organic or inorganic base (e.g. NEt3, diisopropylethylamine, Na 2 C0 3 , Cs 2 C0 3 , K 2 C0 3 ); optionally in the presence of one or more diluents, particularly one or more polar solvents (e.g. Ethyl ace- tate, dichloromethane, DMF, NMP, THF).
  • This type of reaction is also known as acylation (in case R 3 represents alkyl-carbonyl) or alkylation (in case R 3 represents alkyl) typical reaction conditions are known in the field and may applied to the present process.
  • New starting materials and/or intermediates, as well as processes for the preparation thereof, are likewise the subject of this invention.
  • such starting materials are used and reaction conditions so selected as to enable the preferred compounds to be obtained.
  • the invention relates to a process for manufacturing a compound of formula (II),
  • Pg 1 represents a suitable protecting group (e.g. BOC) or hydrogen, with a compound of formula (V),
  • Lg 2 represents a suitable leaving group, such halogen (e.g. chloro, bromo, iodo); optionally in the presence of one or more reaction aids, such as a base (e.g. Na 2 C0 3 , or an inorganic salt (e.g. Kl); optionally in the presence of one or more diluents, particularly polar solvents, (e.g.water, MeCN).
  • halogen e.g. chloro, bromo, iodo
  • reaction aids such as a base (e.g. Na 2 C0 3 , or an inorganic salt (e.g. Kl); optionally in the presence of one or more diluents, particularly polar solvents, (e.g.water, MeCN).
  • This type of reaction is also known as alkylation reaction, typical reaction conditions are known in the field and may applied to the present process.
  • Starting materials of formula (V) are known or obtainable according to known processes; starting materials of formula (IV
  • the invention relates to a process for manufacturing a compound of formula (IV)
  • Lg 3 represents a suitable leaving group, particularly halo , e.g. fluoro with a compound of formula (VII), wherein the substituents are as defined above; followed by the step of reacting the obtained intermediate with a reducing agent, such as hydrogen gas in the presence of a palladium (0) catalyst, or an organometallic salt, such as SnCI 2 followed by reacting the obtained intermediate with a compound of formula (VIII)
  • a reducing agent such as hydrogen gas in the presence of a palladium (0) catalyst, or an organometallic salt, such as SnCI 2
  • Lg 4 represents a suitable leaving group, such as halogen, (e.g. bromo); optionally in the presence of one or more diluents, particular polar solvents (e.g. MeCN).
  • halogen e.g. bromo
  • diluents particular polar solvents (e.g. MeCN).
  • the above described first step is also known as aromatic nucleophilic substitution
  • the above described second step is known as reduction of a nitro to an amino group
  • the above described third step is known as a cyclisation reaction; typical reaction conditions for all steps are known in the field and may applied to the present process.
  • Starting materials of formula (VI), (VII) and (VIII) are known or obtainable according to known processes.
  • the invention relates to a process for manufacturing a compound of formula (IX)
  • Lg 3 represents a suitable leaving group, particularly halo (e.g. fluoro), with a compound of formula (X),
  • Lg 4 is as defined above; optionally in the presence of one or more diluents, particular polar solvents (e.g. MeCN).
  • diluents particular polar solvents (e.g. MeCN).
  • the above described first step is also known as aromatic nucleophilic substitution
  • the above described second step is known as reduction of a nitro to an amino group
  • the above described third step is known as a cyclisation reaction; typical reaction conditions for all steps are known in the field and may applied to the present process.
  • Starting materials of formula (VI) and (VIII) are known or obtainable according to known processes.
  • Starting materials of formula (X) are obtainable according to the processes described herein.
  • the invention relates to a process for manufacturing a compound of formul
  • Pg 3 represents a suitable protecting group (e.g. BOC), with a compound of formula (XII), wherein the substituents are as defined above, optionally in the presence of one or more reaction aids, such as an organic or inorganic base (e.g. NEt 3 , diisopropylethylamine, Na 2 C0 3 , Cs 2 C0 3 , K 2 C0 3 ); optionally in the presence of one or more diluents, particularly one or more polar solvents (e.g. DMF, NMP, THF).
  • reaction aids such as an organic or inorganic base (e.g. NEt 3 , diisopropylethylamine, Na 2 C0 3 , Cs 2 C0 3 , K 2 C0 3 ); optionally in the presence of one or more diluents, particularly one or more polar solvents (e.g. DMF, NMP, THF).
  • This type of reaction is also known as nucleophilic aromatic substitution, typical reaction conditions are known in the field and may applied to the present process.
  • Starting materials of formula (XI) and (XII) are known or readily obtainable.
  • starting materials used in the above described processes are known, capable of being prepared according to known processes, or commercially obtainable; in particular, they can be prepared using processes as described in the Examples.
  • existing functional groups which do not participate in the reaction should, if necessary, be protected. Preferred protecting groups, their introduction and their removal are described above or in the examples.
  • salts thereof may also be used for the reaction, provided that salt-forming groups are present and the reaction with a salt is also possible.
  • the salts thereof are always included, insofar as reasonable and possible.
  • functional groups which are present in the starting materials and are not intended to take part in the reaction are present in protected form if necessary, and protecting groups that are present are cleaved, whereby said starting compounds may also exist in the form of salts provided that a salt-forming group is present and a reaction in salt form is possible.
  • functional groups of the starting compounds which should not take part in the reaction may be present in unprotected form or may be protected for example by one or more protecting groups. The protecting groups are then wholly or partly removed according to one of the known methods.
  • protecting groups and the manner in which they are introduced and removed are described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London, New York 1973, and in “Methoden der organischen Chemie", Houben-Weyl, 4th edition, Vol. 15/1 , Georg-Thieme-Verlag, Stuttgart 1974 and in Theodora W. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York 1981 .
  • a characteristic of protecting groups is that they can be removed readily, i.e. without the occurrence of undesired secondary reactions, for example by solvolysis, reduction, photolysis or alternatively under physiological conditions.
  • any amino group (-NH 2 or -NH) may be protected by a BOC group if the reaction takes place in basic conditions; such BOC group may be removed using a strong acid.
  • any amino group may be protected by an FMOC group if the reaction takes place in acidic conditions; such FMOC group may be removed using a strong acid.
  • a compound of formula (I) obtained may be converted into another compound of formula (I)
  • a free compound of formula (I) may be converted into a salt
  • a salt of a compound of formula (I) may be converted into the free compound or another salt
  • a mixture of isomeric compounds of formula (I) may separated into the individual isomers.
  • the conversion of R 5 to another R 5 e.g. by reduction, substitution and / or oxidation
  • All process steps described here can be carried out under known reaction conditions, preferably under those specifically mentioned, in the absence of or usually in the presence of solvents or diluents, preferably those that are inert to the reagents used and able to dissolve them, in the absence or presence of catalysts, condensing agents or neutralising agents, for example ion exchangers, typically cation exchangers, for example in the H + form, depending on the type of reaction and/or reactants at reduced, normal, or elevated temperature, for example in the range from -100 °C to about 190 °C, preferably from about -80 °C to about 150 °C, for example at -80 to -60 °C, at RT, at - 20 to 40 °C or at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, if need be under pressure, and/or in an inert, for example an argon or nitrogen, atmosphere.
  • solvents or diluents preferably those that are in
  • the invention relates also to those embodiments of the process in which one starts from a compound obtainable at any stage as an intermediate and carries out the missing steps, or breaks off the process at any stage, or forms a starting material under the reaction conditions, or uses said starting material in the form of a reactive derivative or salt, or produces a compound obtainable by means of the process according to the invention under those process conditions, and further processes the said compound in situ.
  • the compounds of formula (I) (or N-oxides thereof), including their salts, are also obtainable in the form of hydrates, or their crystals can include for example the solvent used for crystallisation (present as solvates).
  • a compound of formula (I) is prepared according to the processes and process steps defined in the Examples.
  • the invention relates in a third aspect to the the use of compounds of the present invention as pharmaceuticals.
  • the compounds of formula (I) have valuable pharmacological properties, as described hereinbefore and hereinafter.
  • the invention thus also provides:
  • ⁇ a compound of the formula (I) as defined herein, for the treatment of / for use in the treatment of a disorder or disease selected from multiple myeloma, neuroblastoma, synovial, hepatocellular, Ewing's Sarcoma, adrenocotical carcinoma (ACC) or a solid tumor selected from osteosarcoma, melanoma, tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, lung, uterine or gastrointestinal tumor;
  • a disorder or disease selected from multiple myeloma, neuroblastoma, synovial, hepatocellular, Ewing's Sarcoma, adrenocotical carcinoma (ACC) or a solid tumor selected from osteosarcoma, melanoma, tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, lung, uterine or gastrointestinal tumor;
  • a compound of formula (I) as defined herein for the treatment of a disorder or disease selected from multiple myeloma, neuroblastoma, synovial, hepatocellular,
  • Ewing's Sarcoma adrenocotical carcinoma (ACC) or a solid tumor selected from osteosarcoma, melanoma, tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, lung, uterine or gastrointestinal tumor;
  • ACC adrenocotical carcinoma
  • a solid tumor selected from osteosarcoma, melanoma, tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, lung, uterine or gastrointestinal tumor;
  • ⁇ a method of modulating IGF-1 R activity in a subject, comprising the step of administering to a subject a therapeutically effective amount of a compound of formula (I) as definded herein;
  • a method for inhibition IGF-1 R in a cell comprising contacting said cell with an effective amound of a compound of formula (I) as defined herein.
  • a therapeutically effective amount of a compound of the present invention refers to an amount of the compound of formula (I) that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • a thera-plastically effective amount refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1 ) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder or a disease (i) mediated by IGF-1 R, or (ii) associated with IGF-1 R activity, or (iii) characterized by activity (normal or abnormal) of IGF-1 R; or (2) reducing or inhibiting the activity of IGF-1 R; or (3) reducing or inhibiting the expression of IGF-1 R.
  • a therapeutically effective amount refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biologi- cal material, or a medium, is effective to at least partially reducing or inhibiting the activity of IGF-1 R; or at least partially reducing or inhibiting the expression of IGF-1 R.
  • the meaning of the term "a therapeutically effective amount” as illustrated in the above embodiment for IGF-1 R also applies by the same means to any other relevant pro- teins/peptides/enzymes.
  • An "effective amount” may be determined empirically and in a routine manner, in relation to the stated purpose.
  • the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer.
  • the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic.
  • the term "subject" refers to an animal. Typically the animal is a mammal.
  • a subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like.
  • the subject is a primate.
  • the subject is a human.
  • the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
  • the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • treat refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • “treat”, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • a subject is "in need of” a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • the term “administration” or “administering” of the subject compound means providing a compound of formula (I) and prodrugs thereof to a subject in need of treatment.
  • Administration "in combination with” one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order, and in any route of administration.
  • cancer refers to the physiological condition in mammals that is typically characterized by unregulated cell growth/proliferation. Examples of cancer include, but are not limited to: carcinoma, lymphoma, blastoma, and leukemia.
  • cancers include, but are not limited to: chronic lymphocytic leukemia (CLL), lung, including non small cell (NSCLC), breast, ovarian, cervical, endometrial, prostate, colorec- tal, intestinal carcinoid, bladder, gastric, pancreatic, hepatic (hepatocellular), hepatoblastoma, esophageal, pulmonary adenocarcinoma, mesothelioma, synovial sarcoma, osteosarcoma, head and neck squamous cell carcinoma, juvenile nasopharyngeal angiofibromas, liposarcoma, thyroid, melanoma, basal cell carcinoma (BCC), adrenocotical carcinoma (ACC), medulloblastoma and desmoid.
  • CLL chronic lymphocytic leukemia
  • NSCLC non small cell
  • breast ovarian
  • cervical endometrial
  • prostate colorec- tal
  • IGF-1 R mediated disease includes but is not limited to, multiple myeloma, neuroblastoma, synovial, hepatocellular, Ewing's Sarcoma, adrenocotical carcinoma (ACC), or a solid tumor selected from osteosarcoma, melanoma, tumor of breast, renal, prostate, colorectal, thyroid, ovarian, pancreatic, lung, uterine or gastroin- testinal tumor.
  • compounds of formula (I) are also useful in the treatment of acute lung injury and pulmonary fibrosis.
  • the invention provides in further embodiments methods to treat, ameliorate or prevent a condition which responds to inhibition of IGF-1 R in a mammal suffering from said condition, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) as defined herein, and optionally in combination with a second therapeutic agent.
  • the compounds of the invention may be administered, for example, to a mammal suffering from an autoimmune disease, a transplantation disease, an infectious disease or a cell proliferative disorder.
  • the compounds of the invention may be used alone or in combination with a chemotherapeutic agent to treat a cell proliferative disorder.
  • the invention relates to a process or a method for the treatment of one of the pathological conditions mentioned hereinabove, especially a disease which responds to an inhibition of the IGF-IR tyrosine kinase or of the IGF-IR-dependent cell proliferation, especially a corresponding neoplastic disease.
  • the compounds of formula (I), or a pharmaceutically acceptable salt thereof can be administered as such or in the form of pharmaceutical compositions, prophylactically or therapeutically, preferably in an amount effective against the said diseases, to a warm-blooded animal, for example a human, requiring such treatment, the compounds especially being used in the form of pharmaceutical compositions.
  • the daily dose administered is from approximately 0.1 g to approximately 5 g, preferably from approximately 0.5 g to approximately 2 g, of a compound of the present invention.
  • the invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, especially a compound of formula (I) which is said to be preferred, or a pharmaceutically acceptable salt thereof, as such or in the form of a pharmaceutical composition with at least one pharmaceutically acceptable carrier, for the therapeutic and also prophylactic management of one or more of the diseases mentioned hereinabove, preferably a disease which responds to an inhibition of the IGF- IR tyrosine kinase or of the IGF-IR-dependent cell proliferation, especially a neoplastic disease, in particular if the said disease responds to an inhibition of the IGF-IR tyrosine kinase or of the IGF-IR-dependent cell proliferation.
  • the invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, especially a compound of formula (I) which is said to be preferred, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the therapeutic and also prophylactic management of one or more of the diseases mentioned hereinabove, especially a neoplastic disease, in particular if the disease responds to an inhibition of the IGF-IR tyrosine kinase or of the IGF-IR-dependent cell proliferation.
  • the invention relates in a fourth aspect to pharmaceutical compositions comprising a compound of the present invention. The invention thus provides
  • composition comprising (i.e. containing or consisting of) a compound of formula (I) as defined herein and one or more carriers / excipients;
  • composition comprising a therapeutically effective amount of a compound of formula (I) as defined herein, and one or more pharmaceutically acceptable carriers / excipients.
  • the term "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., anti- bacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329).
  • physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydro- philic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEN®, polyethylene glycol (PEG), and PLURONICS®.
  • buffers such as phosphate, citrate, and other organic acids
  • antioxidants including ascorbic acid
  • proteins such as serum album
  • Suitable excipients / carriers may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
  • Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
  • Compressed gases may be used to disperse a compound of the formula (I) in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • Other suitable pharmaceutical ex- cipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
  • the dosage of the active ingredient depends upon the disease to be treated and upon the species, its age, weight, and individual condition, the individual pharmacokinetic data, and the mode of administration
  • the amount of the compound in a formulation can vary within the full range employed by those skilled in the art.
  • the formulation will contain, on a weight percent (wt%) basis, from about 0.01 -99.99 wt% of a compound of formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
  • the compound is present at a level of about 1 -80 wt%.
  • Unit dose forms are, for example, coated and uncoated tablets, ampoules, vials, suppositories or capsules.
  • compositions for enteral administration such as nasal, buccal, rectal or, especially, oral administration
  • parenteral administration such as intravenous, intramuscular or subcutaneous administration, to warm-blooded animals, especially humans, are especially preferred.
  • the compositions contain the compound of formula (I) alone or, preferably, together with a pharmaceutically acceptable carrier.
  • compositions comprising a compound of formula (I) as defined herein in association with at least one pharmaceutical acceptable carrier (such as an excipient and / or diluent) may be manufactured in conventional manner, e.g. by means of conventional mixing, granulating, coating, dissolving or lyophilising processes.
  • pharmaceutical acceptable carrier such as an excipient and / or diluent
  • the invention relates to a pharmaceutical composition for administration to a warm-blooded animal, especially humans or commercially useful mammals suffering from a disease which responds to an inhibition of the IGF-IR tyrosine kinase or of the IGF-IR-dependent cell proliferation, comprising an effective quantity of a compound of formula (I) for the inhibition of the IGF-IR tyrosine kinase or of the IGF-IR- dependent cell proliferation, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier.
  • a pharmaceutical composition for administration to a warm-blooded animal especially humans or commercially useful mammals suffering from a disease which responds to an inhibition of the IGF-IR tyrosine kinase or of the IGF-IR-dependent cell proliferation
  • an effective quantity of a compound of formula (I) for the inhibition of the IGF-IR tyrosine kinase or of the IGF-IR- dependent cell proliferation or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable
  • the invention relates to a pharmaceutical composition for the prophylactic or especially therapeutic management of neoplastic and other proliferative diseases of a warm-blooded animal, especially a human or a commercially useful mammal requiring such treatment, especially suffering from such a disease, comprising as active ingredient in a quantity that is prophylactically or especially therapeutically active against said diseases a new compound of formula (I), or a pharmaceutically acceptable salt thereof, is likewise preferred.
  • the invention relates in a fifth aspect to combinations comprising a compound of formula (I) and one or more additional active ingredients.
  • the invention thus provides
  • a combination in particular a pharmaceutical combination comprising a therapeutically effective amount of a compound of formula (I) and one or more therapeutically active agents, particularly antiproliferative agents;
  • a combined pharmaceutical composition adapted for simultaneous or sequential administration, comprising a therapeutically effective amount of a compound of formula (I) as defined herein; therapeutically effective amount(s) of one or more combination partners, particularly antiproliferative agents; one or more pharmaceutically acceptable excepients;
  • composition as defined herein (i) as pharmaceutical, (ii) for use in the treatment of a IGF-1 R mediated disease, (iii) in a method of treatment of a IGF-1 R mediated disease.
  • the term “combination” refers to either a fixed combination in one dosage unit form, or a kit of parts for the combined administration where a compound of the formula (I) and a combination partner (e.g. an other drug as explained below, also referred to as “therapeutic agent” or “co-agent”) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect.
  • a combination partner e.g. an other drug as explained below, also referred to as “therapeutic agent” or “co-agent”
  • co-agent e.g. an other drug as explained below, also referred to as “therapeutic agent” or “co-agent”
  • pharmaceutical combination means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a compound of formula (I) and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g.
  • a compound of formula (I) and a combination partner are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • antiproliferative agent includes, but are not limited to, aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, alkylating agents, histone deacetylase inhibitors, farnesyl transferase inhibitors, COX-2 inhibitors, MMP inhibitors, compounds decreasing the lipid kinase activity, eg PI3 kinase inhibitors, antineoplastic antimetabolites, platin compounds, compounds decreasing the protein kinase activity, eg mTOR inhibitors, Raf inhibitors, MEK inhibitors, and further anti-angiogenic compounds, gonadorelin agonists, anti-androgens, bengamides, bisphosphonates and trastuzumab, radiotherapy.
  • aromatase inhibitors as used herein relates to compounds which inhibit the estrogen production, i.e. the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.
  • the term includes, but is not limited to steroids, especially exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, vorozole, fadrozole, anastrozole and, very especially, letrozole.
  • Exemestane can be administered, e.g., in the form as it is marketed, e.g. under the trademark AROMASINTM.
  • Formestane can be administered, e.g., in the form as it is marketed, e.g.
  • Fadrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark AFEMATM.
  • Anastrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark ARIMIDEXTM.
  • Letrozole can be administered, e.g., in the form as it is marketed, e.g. under the trademark FEMARATM or FEMARTM.
  • Aminoglutethimide can be administered, e.g., in the form as it is marketed, e.g. under the trademark ORIMETENTM.
  • a combination of the invention comprising an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive breast tumors.
  • antiestrogens as used herein relates to compounds which antagonize the effect of estrogens at the estrogen receptor level.
  • the term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride.
  • Tamoxifen can be administered, e.g., in the form as it is marketed, e.g. under the trademark NOLVADEXTM.
  • Raloxifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g. under the trademark EVISTATM.
  • Fulvestrant can be formulated as disclosed in US 4,659,516 or it can be administered, e.g., in the form as it is marketed, e.g. under the trademark FASLODEXTM.
  • topoisomerase I inhibitors includes, but is not limited to topotecan, irinotecan, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound A1 in WO99/17804).
  • Irinotecan can be administered, e.g., in the form as it is marketed, e.g. under the trademark CAMPTOSARTM.
  • Topotecan can be administered, e.g., in the form as it is marketed, e.g. under the trademark HYCAMTINTM.
  • topoisomerase II inhibitors includes, but is not limited to the antracyclines doxorubicin (including liposomal formulation, e.g. CAELYXTM), epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide.
  • Etoposide can be administered, e.g., in the form as it is marketed, e.g. under the trademark ETOPOPHOSTM.
  • Teniposide can be administered, e.g., in the form as it is marketed, e.g. under the trademark VM 26- BRISTOLTM.
  • Doxorubicin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ADRIBLASTINTM.
  • Epirubicin can be administered, e.g., in the form as it is marketed, e.g. under the trademark FARMORUBICINTM.
  • Idarubicin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ZAVEDOSTM.
  • Mitoxantrone can be administered, e.g., in the form as it is marketed, e.g. under the trademark NOVANTRONTM.
  • lipid kinase inhibitors relates to PI3 kinase inhibitors, PI4 kinase inhibitors, Vps34 inhibitors.
  • Specific examples include: NVP-BEZ235, NVP-BGT226, NVP- BKM120, AS-604850, AS-041 164, AS-252424, AS-605240, GDC0941 , PI-103, TGX221 , YM201636, ZSTK474, examples described in WO 2009/080705 and US 2009/163469.
  • microtubule active agents relates to microtubule stabilizing and microtubule destabilizing agents including, but not limited to the taxanes paclitaxel and docetaxel, the vinca alkaloids, e.g., vinblastine, especially vinblastine sulfate, vincristine especially vincristine sulfate, and vinorelbine, discodermolide and epothilones, such as epothilone B and D.
  • Docetaxel can be administered, e.g., in the form as it is marketed, e.g. under the trademark TAXOTERETM.
  • Vinblastine sulfate can be administered, e.g., in the form as it is marketed, e.g. under the trademark VINBLASTIN R.P.TM.
  • Vincristine sulfate can be administered, e.g., in the form as it is marketed, e.g. under the trademark FARMISTIN TM.
  • Discodermolide can be obtained, e.g., as disclosed in US 5,010,099.
  • alkylating agents includes, but is not limited to cyclophos- phamide, ifosfamide and melphalan.
  • Cyclophosphamide can be administered, e.g., in the form as it is marketed, e.g. under the trademark CYCLOSTINTM.
  • Ifosfamide can be administered, e.g., in the form as it is marketed, e.g. under the trademark HOLOXANTM.
  • histone deacetylase inhibitors relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity.
  • farnesyl transferase inhibitors relates to compounds which inhibit the farnesyl transferase and which possess antiproliferative activity.
  • COX-2 inhibitors relates to compounds which inhibit the cyclooxygenase type 2 enyzme (COX-2) and which possess antiproliferative activity such as celecoxib (Celebrex®) and rofecoxib (Vioxx®).
  • MMP inhibitors relates to compounds which inhibit the matrix metalloproteinase (MMP) and which possess antiproliferative activity.
  • mTOR inhibitors relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (CerticanTM), CCI-779 and ABT578.
  • antimetabolites includes, but is not limited to 5-fluorouracil, 5- fluorouracil, tegafur, capecitabine, cladribine, cytarabine, fludarabine phosphate, fluorouridine, gemcitabine, 6-mercaptopurine, hydroxyurea, methotrexate, edatrexate and salts of such compounds, and furthermore ZD 1694 (RALTITREXEDTM), LY231514 (ALIMTATM), LY264618 (LOMOTREXOLTM) and OGT719.
  • platinum compounds as used herein includes, but is not limited to carboplatin, cis-platin and oxaliplatin.
  • Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark CARBOPLATTM.
  • Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark ELOXATINTM.
  • compounds decreasing the protein kinase activity and further anti-angiogenic compounds as used herein includes, but is not limited to compounds which decrease the activity of e.g. the Vascular Endothelial Growth Factor (VEGF), the Epidermal Growth Factor (EGF), and c-Src and and anti-angiogenic compounds having another mechanism of action than decreasing the protein kinase activity.
  • VEGF Vascular Endothelial Growth Factor
  • EGF Epidermal Growth Factor
  • c-Src c-Src and and
  • Compounds which decrease the activity of VEGF are especially compounds which inhibit the VEGF receptor, especially the tyrosine kinase activity of the VEGF receptor, and compounds binding to VEGF, and are in particular those compounds, proteins and monoclonal antibodies generically and specifically disclosed in WO 98/35958 (describing compounds of formula (I)), WO 00/09495, WO 00/27820, WO 00/59509, WO 98/1 1223, WO 00/27819, WO 01/551 14, WO 01/58899 and EP 0 769 947; those as described by M. Prewett et al in Cancer Research 59 (1999) 5209-5218, by F. Yuan et al in Proc. Natl.
  • Compounds which decrease the activity of EGF are especially compounds which inhibit the EGF receptors, especially the tyrosine kinase activity of the EGF receptors, and compounds binding to EGF, and are in particular those compounds generically and specifically disclosed in WO 97/02266 (describing compounds of formula (l)V), EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and, especially, WO 96/33980.
  • EGF receptor inhibitor examples include, but not limited to; Tarceva (erlotinib), Iressa (Gefitinib), Tywerb (lapatanib). Erbitux (cetuximab), Avastin (bevacizumab), Herceptin (trastuzamab), Rituxan (rituximab), Bexxar (tositumomab), panitumumab.
  • Compounds which decrease the activity of c-Src include, but are not limited to, compounds inhibiting the c-Src protein tyrosine kinase activity as defined below and to SH2 interaction inhibitors such as those disclosed in WO97/07131 and WO97/08193; compounds inhibiting the c-Src protein tyrosine kinase activity include, but are not limited to, compounds belonging to the structure classes of pyrrolopyrimidines, especially pyrrolo[2,3-d]pyrimidines, purines, pyrazopyrimidines, especially pyrazo[3,4- d]pyrimidines, pyrazopyrimidines, especially pyrazo[3,4-d]pyrimidines and pyridopyrimidines, especially pyrido[2,3-d]pyrimidines.
  • the term relates to those compounds disclosed in WO 96/10028, WO 97/28161 , W097/32879 and WO97/497
  • Raf kinases Compounds which decrease the activity of Raf kinases include, but are not limited to: Raf265, sorefanib, BAY 43-9006.
  • MEK inhibitors include; PD 98059, AZD6244 (ARRY-886), CI-1040, PD 0325901 , U0126.
  • Anti-angiogenic compounds having another mechanism of action than decreasing the protein kinase activity include, but are not limited to e.g. thalidomide (THALOMIDTM), SU5416, and celecoxib (CelebrexTM).
  • TAALOMIDTM thalidomide
  • CelebrexTM celecoxib
  • gonadorelin agonist includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin is disclosed in US 4, 100,274 and can be administered, e.g., in the form as it is marketed, e.g. under the trademark ZOLADEXTM.
  • anti-androgens as used herein includes, but is not limited to bicalutamide (CASODEXTM), which can be formulated, e.g. as disclosed in US 4,636,505.
  • bengamides relates to bengamides and derivatives thereof having aniproliferative properties and includes, but is not limited to the compounds generically and specifically disclosed in WO00/29382, preferably to ex.1 of WO00/29382.
  • bisphosphonates as used herein includes, but is not limited to etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid and zoledronic acid.
  • etridonic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark DIDRONELTM.
  • Clodronic acid can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONEFOSTM.
  • "Tiludronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark SKELIDTM.
  • “Pamidronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark AREDIATM.
  • “Alendronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark FOSAMAXTM.
  • “Ibandronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark BONDRANATTM.
  • “Risedronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark ACTONELTM.
  • "Zoledronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the trademark ZOMETATM.
  • trastuzumab can be administered, e.g., in the form as it is marketed, e.g. under the trademark HERCEPTINTM.
  • HATU (2-(7-Aza-1 H-benzotriazole-1- yl)-1 , 1 ,3,3-tetramethyluronium- hexafluorophosphate)
  • HPLC/MS Method D Instrument Waters Acquity Ultra Performance LC system, Waters 2996 photodiode array UV detector, Water SQ MS detector (range: 130-750 amu; cone: +10V and -30V), column oven temperature +40°C.
  • step N.1 4-Hydroxymethyl-indole-1 -carboxylic acid tert-butyl ester (step N.1 , 17.0 g, 68.7 mmol) in CH2CI2 (229 ml) was added tetrabromomethane (25.1 g, 76 mmol) and the yellow clear solution cooled to 0 °C.
  • triphenylphosphine (27.0 g, 103 mmol) was added in portions over the course of 10 minutes. The resulting mixture was stirred at 0 °C for 1 hr. The mixture was then treated with water (150 mL) and the medium was vigorously stirred for an hour at rt.
  • Step N.1 4-Hydroxymethyl-indole-1-carboxylic acid tert-butyl ester
  • step N.2 To a solution of indole-1 ,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (step N.2, 20.0 g, 72.6 mmol) in THF (363 ml) at -78°C under Ar was added DIBAL-H 1 M in cyclo- hexane (145.0 ml, 145 mmol) dropwise. The resulting solution was stirred at -78°C for 20 minutes, allowed to reach rt slowly and then stirred at rt temperature for 16 hours. The reaction mixture was then cooled to 0°C and Rochelle's salt solution (200 ml.) was care- fully added (strong exotherm). The resulting mixture was stirred for 2 hours.
  • Step N.2 lndole-1 ,4-dicarboxylic acid 1 -tert-butyl ester 4-methyl ester
  • Step AG3 1 H-Benzoimidazole-4-carboxylic acid methyl ester
  • Step AH1 4-hydroxymethyl-benzotriazole-1 -carboxylic acid tert-butyl ester
  • CH 2 CI 2 4-hydroxymethyl-benzotriazole-1 -carboxylic acid tert-butyl ester
  • triphenylphosphine 2.494 g, 9.51 mmol
  • the mixture was chilled to 0 °C then a solution of CBr4 (3.15 g, 9.51 mmol) in CH 2 CI 2 (24.00 mL) was added dropwise and stirring was maintained at 0 °C for 1.5 hrs.
  • Step AH1 4-Hvdroxvmethvl-benzotriazole-1 -carboxvlic acid tert-butyl ester
  • Step AM 4-(2-Amino-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester
  • MeCN MeCN
  • water 10.4 ml_
  • cyanogen bromide 5M solution in MeCN, 3.49 ml_, 17.5 mmol
  • the reaction mixture was concentrated under vacuum, diluted with EtOAc (100 ml.) and washed successively with saturated aqueous sodium bicarbonate solution (3 x 100 ml.) and brine (1 x 100ml_).
  • Step AN1 618 mg, 1.35 mmol
  • CH 2 CI 2 7 mL
  • a solution of TFA 3.1 1 mL, 40 mmol
  • water 0.06 mL
  • the mixture was stirred at rt for 1 h. All volatiles were removed under vacuum and the oily residue was azeotroped with toluene (3 x 30 mL) to give a dark brown oily substance.
  • the crude material was dissolved in a mixture of CH 2 CI 2 (30 mL) and methanol (2 mL).
  • Step AN1 4-[3-(2-Chloro-benzyl)-6-fluoro-2-imino-2,3-dihydro-benzoimidazol-1 -yl]- piperidine-1 -carboxylic acid tert-butyl ester
  • the crude solid product was purified by chromatography on silica gel, using a 0% to 100% gradient of eluent B (CH 2 CI 2 /MeOH : 8/2) in eluent A (CH 2 CI 2 ), yielding the title product , 88 mg, and unreacted starting material, 413 mg.
  • the recovered starting material was reacted with 1 eq. 2-chlorobenzyl bromide in MeCN at 1 10°C for 30 min. An additional 0.3 eq. of 2-chlorobenzyl bromide was added and the mixture was stirred at rt for 48h.
  • the product was purified by chromatography on silica gel, using a 0% to 100% gradient of eluent B (CH 2 CI 2 /MeOH : 8/2) in eluent A (CH 2 CI 2 ), yielding the title product, 526 mg, for a combined yield of 614 mg (71 %).
  • step 1 To a suspension of 1 -(1-m-Tolyl-piperidin-4-yl)-1 H-benzoimidazol-2-ylamine (step 1 , 50 mg, 0.163 mmol) in MeCN (2.0 mL) were added 2-chlorobenzylbromide (21.3 ⁇ _, 0.163 mmol) and Kl (27.6 mg, 0.163 mmol). The resulting mixture was heated to 1 10°C for 10 minutes under microwave irradiation. The medium was then evaporated to dryness and the residue partitionned between water (6 mL) and EtOAc (5 mL). The organic phase was separated and the aqueous layer was further extracted with EtOAc (2 x 5 mL).
  • Step 1 1-(1-m-Tolyl-piperidin-4-yl)-1 H-benzoimidazol-2-ylamine
  • step 1 To a suspension of N- ⁇ 2-[4-(2-Amino-benzoimidazol-1-yl)-piperidin-1-yl]-4-methyl- phenyl ⁇ -acetamide (step 1 , 50.0 mg, 0.13 mmol) in MeCN (1.3 mL) were added Kl (22.0 mg, 0.13 mmol) and intermediate N (45.0 mg, 0.13 mmol). The reaction vessel was sealed and the reaction mixture was placed on a plate pre heated to 1 10°C and stirred at this temperature for 30 minutes. The reaction mixture wasthen cooled to rt and filtered, washing the solid cake with CH 2 CI 2 (2 x 3 mL). The filtrate was then evaporated to dryness to furnish the product as a crude residue.
  • the residue was purified by reverse- phase preparative HPLC (Method E, using a gradient elution of (MeCN +0.1 % TFA) in (Water +0.1 % TFA)). Product-containing fractions were pooled and evaporated to dryness.
  • the residue was treated with a CH 2 CI 2 / ( TFA Water 98/2) : 7/3 solution (2 mL) for 1 hour at rt to remove the Boc protecting group.
  • the medium was evaporated to dryness and partitioned between CH 2 CI 2 (2 mL) and saturated aqueous sodium bicarbonate solution (2 mL). The organic layer was separated, dried and evaporated to dryness to furnish the title compound as an off-white solid, 13.0 mg (20%).
  • step 1 dihydro-benzoimidazol-1 -ylmethyl ⁇ -indole-1-carboxylic acid tert-butyl ester (step 1 , 62 mg, 0.092 mmol) was dissolved in EtOAc (1 .84 mL) and acetyl chloride (6.54 ⁇ _, 0.092 mmol) was added.
  • EtOAc 1 .84 mL
  • acetyl chloride (6.54 ⁇ _, 0.092 mmol) was added.
  • the reaction vessel was sealed and placed in a 80°C-pre-heated oil bath. Stirring was performed for 1 hour before evaporation of the volatiles under reduced pressure.
  • the crude mixture was purified by reverse-phase preparative HPLC (Method E, gradient from 60% (MeOH/MeCN 3/1 +0.1 % TFA) in (Water +0.1 % TFA) to 90% over 14 minutes).
  • Step 1 4- ⁇ 3-[1 -(2-Amino-5-chloro-phenyl)-piperidin-4-yl]-2-[tert-butoxycarbonylimino]-2,3- dihydro-benzoimidazol-1 -ylmethyl ⁇ -indole-1-carboxylic acid tert-butyl ester
  • Step 2 4- ⁇ 2-[tert-Butoxycarbonylimino]-3-[1-(5-chloro-2-nitro-phenyl)-piperidin-4-yl]-2,3- dihydro-benzoimidazol-1 -ylmethyl ⁇ -indole-1-carboxylic acid tert-butyl ester
  • Step 3 1-[1-(5-Chloro-2-nitro-phenyl)-piperidin-4-yl]-3-(1 H-indol-4-ylmethyl)-1 ,3-dihydro- benzoimidazol-2-ylideneamine
  • Step 5 4-[3-(1-tert-Butoxycarbonyl-piperidin-4-yl)-2-imino-2,3-dihydro-benzoimidazol-1- ylmethyl]-indole-1 -carboxylic acid tert-butyl ester
  • step 1 4-Chloro-2- ⁇ 4-[3-(2-chloro-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-piperidin-1 - yl ⁇ -phenylamine (step 1 , 292 mg, 0.626 mmol) was dissolved in EtOAc (2.50 ml.) and acetyl chloride (44.5 ⁇ _, 0.626 mmol) was added. The reaction vessel was sealed and placed in a 80°C-pre-heated oil bath. Stirring was performed for 1 hour before evaporation of the volatiles under reduced pressure.
  • Step 2 1-(2-Chloro-benzyl)-3-[1-(5-chloro-2-nitro-phenyl)-piperidin-4-yl]-1 ,3-dihydro-
  • Step 4 4-[3-(2-Chloro-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-piperidine-1 - carboxylic acid tert-butyl ester
  • step 1 171 mg, 0.231 mmol
  • MeOH 2.31 mL
  • tin (II) chloride dihydrate 156 mg, 0.693 mmol
  • the resulting mixture was stirred at rt for 22 hours. More tin (II) chloride dihydrate (156 mg, 0.693 mmol) was added and the reaction was heated up to 50°C for 8 hours.
  • the mixture was allowed to cool to rt and was carefully quenched with saturated aqueous sodium bicarbonate solution (4 mL). The resulting paste was shaken for 15 minutes at rt.
  • the crude residue was purified by reverse-phase preparative HPLC (Method E, gradient from 40% (MeOH/MeCN 3/1 +0.1 % TFA) in (Water +0.1 % TFA) to 70% over 14 minutes).
  • Product-containing fractions were pooled and evaporated to dryness.
  • the residue was then treated with a TFA/DCM 1/3 solution for 1 hour at rt before evaporation to dryness.
  • the resulting crude product was purified a second time by reverse-phase preparative HPLC (Method E, gradient from 40% (MeOH/MeCN 3/1 +0.1 % TFA) in (Water +0.1 % TFA) to 70% over 14 minutes).
  • Step 1 4- ⁇ 2-tert-Butoxycarbonylimino-3-[1-(5-chloro-2-nitro-p ⁇
  • Step 2 1 -(1 H-Benzotriazol-4-ylmethyl)-3-[1 -(5-chloro-2-nitro-phenyl)-piperidin-4-yl]-1 ,3- dihydro-benzoimidazol-2-ylideneamine
  • Example 65 N- ⁇ 4-[6-Fluoro-2-imino-3-(1 H-indol-4-ylmethyl)-2,3-dihydro-benzoimidazol- 1-yl]-6'-methyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-3'-yl ⁇ -acetamide
  • Example 66 N-(2- ⁇ 4-[2-Acetylimino-3-(1 H-indol-4-ylmethyl)-2,3-dihydro-benzoimidazol-1- yl]-piperidin-1-yl ⁇ -4-methyl-phenyl)-acetamide
  • step 1 benzoimidazol-1-ylmethyl ⁇ -indole-1-carboxylic acid tert-butyl ester (step 1 , 65 mg, 0.1 10 mmol) was dissolved in EtOAc (500 ⁇ ) and AcCI (1 1 .70 ⁇ , 0.164 mmol) was added. The reaction vessel was sealed, placed on a 80°C pre-heated plate and stirred at 80°C for 30 min. Further AcCI (3.9 ⁇ , 0.054 mmol) was added and the reaction mixture was stirred at 80°C for another 30 minutes. The medium was allowed to cool down, MeOH (2 mL) was added and the resulting solution was evaporated to dryness.
  • Step 1 4- ⁇ 3-[1-(2-Acetylamino-5-methyl-phenyl)-piperidin-4-yl]-2-imino-2,3-dihydro- benzoimidazol-1-ylmethyl ⁇ -indole-1-carboxylic acid tert-butyl ester
  • the vessel was sealed and placed on a 80°C pre-heated plate and stirred at this temperature for 30 minutes. The reaction was then allowed to cool down to rt. The mixture was diluted with MeOH (1 ml.) and the resulting clear solution was stirred for 30 minutes. The volatile materials were removed under reduced pressure and the residue was dried under high vacuum. The residue was then treated with TFA (1000 ⁇ _, 12.98 mmol) and the resulting solution was shaken for 5 minutes at rt. The reaction was then quenched with MeOH (1 ml.) and water (1 ml_). NEt 3 (1 ml.) was cautiously added and the resulting solution was treated with saturated aqueous sodium bicarbonate solution (5 ml_).
  • Step 1 Rac-frans-4- ⁇ 3-[3-Acetoxy-1-(2-amino-5-chloro-phenyl)-piperidin-4-yl]-2-tert- butoxycarbonylimino-5-fluoro-2,3-dihydro-benzoimidazol-1-ylmethyl ⁇ -indole-1-carboxylic acid tert-butyl ester
  • Step 3 Rac-frans-4- ⁇ 3-[3-Acetoxy-1 -(5-chloro-2-nitro-phenyl)-piperidin-4-yl]-5-fluoro-2- imino-2,3-dihydro-benzoimidazol-1-ylmethyl ⁇ -indole-1-carboxylic acid tert-butyl ester
  • Step 5 Rac-frans-acetic acid-4-(2-amino-6-fluoro-benzoimidazol-1 -yl)-piperidin-3-yl ester
  • Step 7 Rac-frans-3-Acetoxy-4-(2-amino-5-fluoro-phenylamino)-piperidine-1 -carboxylic
  • Step 8 Rac-frans-3-acetoxy-4-(5-fluoro-2-nitro-phenylamino)-piperidine-1-carboxylic acid
  • Step 9 Rac-frans-4-(5-fluoro-2-nitro-phenylamino)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester
  • step 1 1 To a solution of 3,6-Dihydro-2H-pyridine-1 -carboxylic acid tert-butyl ester (step 1 1 , 7.1 g, 38.7 mmol) in CH 2 CI 2 (77 mL) at 0 °C was added mCPBA (8.68 g, 38.7 mmol) in portions. The resulting clear solution was stirred at 0 °C for 20 min. The medium was then allowed to reach rt. After 3 hours of stirring ar rt, further mCPBA (4.34 g, 19.37 mmol) was added. The medium was stirred at rt for an additional 16 hours.
  • the medium was then diluted with Et20 (500 mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 200 mL) and brine (250 mL). The organic phase was dried over Na 2 S0 4 and concentrated to give a crude brown oil, 9.7 g.
  • the crude oil was dissolved in EtOH (183 ml) and sodium azide (1 1 .87 g, 183 mmol), magnesium sulfate (10.99 g, 91 mmol) and water (3.29 ml, 183 mmol) were successively added.
  • the resulting suspension was ref- luxed for 16 hr.The medium was then cooled in an ice bath and filtered.
  • Examples 67.1 to 67.7 were synthesized in a manner analogous to that used for the synthesis of example 67, using a combination of the following modifications: 2-fluoro-6- methyl-3-nitropyridine instead of 2-fluoro-4-chloro-1 -nitro-benzene in step 4; 2-fluoro-1- nitro-benzene instead of 2, 4-difluoro-1 -nitrobenzene in step 9; and either 2-chlorobenzyl bromide or intermediate AH or intermediate AG instead of intermediate N in step 3.
  • Example 77 N- ⁇ 6'-Chloro-4-[3-(2-chloro-benzyl)-6-fluoro-2-imino-2,3-dihydro- benzoimidazol-1-yl]-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-3'-yl ⁇ -acetamide
  • Example 78 N- ⁇ 4-[3-(2-Chloro-benzyl)-6-fluoro-2-imino-2,3-dihydro-benzoimidazol-1 -yl]- 6'-methyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-3'-yl ⁇ -acetamide
  • Step 1 4-[3-(2-Chloro-benzyl)-6-fluoro-2-imino-2,3-dihydro-benzoimidazol-1-yl]-6'- methyl-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-3'-ylamine
  • BaF3-Tel-IGF1 -R and BaF3-lnsR are BaF3 murine proB-cell lymphoma cell derivatives [the BaF3 cell line (also termed Ba/F3) is available from the German Collection of Microorganisms and Cell Cultures (DSMZ), Braunschweig, Germany] that have been rendered IL-3-independent by stable transduction with kinase-activating fusions between human TEL (aa 1-452) and the kinase domain of IGF-1 R (aa 976-1367) linked by a Ser-Arg- linker (Boulay et al, Cancer Res 68, 3743-3751 , 2008), and a fusion between human TEL (aa 1-337) and the kinase domain (aa 1015-1382) of the Insulin receptor (Melnick
  • Cells are cultured in RPMI-1640 (Animed # 1-14F01 -I) supplemented with 2 % L-glutamine (Animed # 5- 10K50-H) and 10 % fetal calf serum (FCS, Animed # 2-01 F16-I).
  • Wild-type, untrans- fected BaF3 cells are maintained in above medium plus 10 U/ml IL-3 (mouse Interleukin- 3, Roche # 1380745 or Invitrogen # PMC0035) and are used to identify non-selective, generally growth-inhibitory compounds.
  • Cells (1.5 x 10 4 cells per well) are seeded in 190 ⁇ fresh medium into 96-well plates. 10 ⁇ 20x compound solutions are added.
  • the kinase inhibitor PKC412 is routinely used as internal control.
  • Control cells treated with DMSO (0.1 % final concentration) serve as growth reference (set as 100% growth).
  • a plate blank value is routinely determined in a well containing only 100 ⁇ of medium and no cells. IC 50 determinations are performed based on eight 3-fold serial dilutions of the test compound, starting at 10 ⁇ . Following incubation of the cells for 48 h at 37°C and 5% C0 2 , the effect of inhibitors on cell viability is assessed by the resazurin sodium salt dye reduction assay (commercially known as AlamarBlue assay) basically as previously described (O'Brien J. et al., Eur. J. Biochem.
  • the cell viability assay can also be performed in a 384- well format. Briefly, 4'500 freshly diluted cells are seeded in 54 ⁇ /well into 384-well plates using a liquid dispenser. 6 ⁇ 10x compound solution is added to the cell plate. As internal control, the kinase inhibitor PKC412 is routinely used. Control cells treated with DMSO (0.1 % final concentration) serve as growth reference (set as 100% growth). In addition, a plate blank value is routinely determined in a well containing only 60 ⁇ of medium and no cells. Dose-response effects are determined by 3-fold serial compound dilutions, starting at 10 ⁇ .
  • Tablets comprising 50 mg of active ingredient, of the compounds of formula (I) described in Examples 1 to 88, and having the following composition are prepared in customary manner:
  • composition active ingredient 50 mg
  • colloidal silicic acid 12.5 mg
  • Preparation The active ingredient is mixed with a portion of the wheat starch, with the lactose and the colloidal silicic acid and the mixture is forced through a sieve. A further portion of the wheat starch is made into a paste, on a water bath, with five times the amount of water and the powder mixture is kneaded with the paste until a slightly plastic mass is obtained. The plastic mass is pressed through a sieve of about 3 mm mesh size and dried, and the resulting dry granules are again forced through a sieve. Then the remainder of the wheat starch, the talc and the magnesium stearate are mixed in and the mixture is compressed to form tablets weighing 145 mg and having a breaking notch.
  • the pulverized active ingredient is suspended in Lauroglykol® (propylene glycol laurate, Gattefosse S.A., Saint Priest, France) and ground in a wet pulverizer to a particle size of approx. 1 to 3 ⁇ . 0.419 g portions of the mixture are then dispensed into soft gelatin capsules using a capsule-filling machine.
  • Lauroglykol® propylene glycol laurate, Gattefosse S.A., Saint Priest, France

Abstract

La présente invention concerne de nouveaux dérivés de formule (I) dans laquelle les substituants sont tels que définis dans le mémoire ; des procédés de préparation desdits dérivés ; des compositions pharmaceutiques contenant lesdits dérivés ; lesdits dérivés en tant que médicament ; lesdits dérivés pour le traitement d'un ou plusieurs troubles ou maladies médiés par l'IGF-1R.
PCT/EP2011/060032 2010-06-17 2011-06-16 Dérivés de 1,3‑dihydro-benzoimidazol-2-ylidène-amine à substitution pipéridinyle WO2011157793A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CN201180029739XA CN102947275A (zh) 2010-06-17 2011-06-16 哌啶基取代的1,3-二氢-苯并咪唑-2-亚基胺衍生物
EP11725116.5A EP2582681A1 (fr) 2010-06-17 2011-06-16 Dérivés de 1,3 dihydro-benzoimidazol-2-ylidène-amine à substitution pipéridinyle
US13/704,380 US20130085161A1 (en) 2010-06-17 2011-06-16 Piperidinyl substituted 1,3-dihydro-benzoimidazol-2-ylideneamine derivatives
JP2013514720A JP2013532149A (ja) 2010-06-17 2011-06-16 ピペリジニル置換１，３−ジヒドロ−ベンゾイミダゾール−２−イリデンアミン誘導体

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US35584510P 2010-06-17 2010-06-17
US61/355,845 2010-06-17

Publications (1)

Publication Number Publication Date
WO2011157793A1 true WO2011157793A1 (fr) 2011-12-22

Family

ID=44562669

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2011/060032 WO2011157793A1 (fr) 2010-06-17 2011-06-16 Dérivés de 1,3‑dihydro-benzoimidazol-2-ylidène-amine à substitution pipéridinyle

Country Status (5)

Country Link
US (1) US20130085161A1 (fr)
EP (1) EP2582681A1 (fr)
JP (1) JP2013532149A (fr)
CN (1) CN102947275A (fr)
WO (1) WO2011157793A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014177977A1 (fr) 2013-05-02 2014-11-06 Pfizer Inc. Dérivés d'imidazo-triazine utilisés comme inhibiteurs de la pde10
US11873298B2 (en) 2017-10-24 2024-01-16 Janssen Pharmaceutica Nv Compounds and uses thereof

Citations (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4004016A (en) * 1975-08-11 1977-01-18 E. R. Squibb & Sons, Inc. Amino-benzimidazole derivatives
US4100274A (en) 1976-05-11 1978-07-11 Imperial Chemical Industries Limited Polypeptide
EP0039051A2 (fr) 1980-04-24 1981-11-04 Merck & Co. Inc. Derivés des acides hydroxamiques de type des N-bases de Mannich servant comme composés de départ pour la biodisponibilité d'agents anti-inflammatoires non-stéroidiques, procédé de préparation et composition pharmaceutique les contenant
US4636505A (en) 1982-07-23 1987-01-13 Imperial Chemical Industries Plc Amide derivatives
US4659516A (en) 1983-10-12 1987-04-21 Imperial Chemical Industries Plc Steroid derivatives
US5010099A (en) 1989-08-11 1991-04-23 Harbor Branch Oceanographic Institution, Inc. Discodermolide compounds, compositions containing same and method of preparation and use
EP0520722A1 (fr) 1991-06-28 1992-12-30 Zeneca Limited Préparations thérapeutiques contenant des dérivés de quinazoline
EP0564409A1 (fr) 1992-04-03 1993-10-06 Ciba-Geigy Ag Dérivés de pyrimidine et procédé pour leur préparation
EP0566226A1 (fr) 1992-01-20 1993-10-20 Zeneca Limited Dérivés de quinazoline
WO1994010202A1 (fr) 1992-10-28 1994-05-11 Genentech, Inc. Antagonistes du facteur de croissance des cellules endotheliales vasculaires
WO1996010028A1 (fr) 1994-09-29 1996-04-04 Novartis Ag PYRROLO[2,3-d]PYRIMIDINES ET LEUR UTILISATION
WO1996033980A1 (fr) 1995-04-27 1996-10-31 Zeneca Limited Derives de quinazoline
WO1997002266A1 (fr) 1995-07-06 1997-01-23 Novartis Ag Pyrrolopyrimidines et leurs procedes de preparation
WO1997007131A1 (fr) 1995-08-17 1997-02-27 Novartis Ag Oligopeptides acyles divers
WO1997008193A1 (fr) 1995-08-17 1997-03-06 Novartis Ag Derives oligopeptidiques acyles presentant une activite inhibant des signaux cellulaires
EP0769947A1 (fr) 1995-06-07 1997-05-02 Sugen, Inc. Composes d'indolinone pour le traitement de maladies
EP0787722A1 (fr) 1996-02-05 1997-08-06 American Cyanamid Company Dérivés de quinazoline substitués
WO1997028161A1 (fr) 1996-02-01 1997-08-07 Novartis Ag Nouvelles pyrrolo(2,3-d)pyrimidines et leur utilisation en tant qu'inhibiteurs de tyrosine kinase
WO1997030034A1 (fr) 1996-02-14 1997-08-21 Zeneca Limited Derives de la quinazoline servant d'agents antitumoraux
WO1997032879A1 (fr) 1996-03-06 1997-09-12 Novartis Ag 7-ALKYLE-PYRROLO[2,3-d]PYRIMIDINES
WO1997038983A1 (fr) 1996-04-12 1997-10-23 Warner-Lambert Company Inhibiteurs irreversibles de tyrosine kinases
WO1997049688A1 (fr) 1996-06-24 1997-12-31 Pfizer Inc. Derives tricycliques substitues par phenylamino, destines au traitement des maladies hyperproliferatives
WO1997049706A1 (fr) 1996-06-25 1997-12-31 Novartis Ag 7-AMINO-PYRROLO[3,2-d]PYRIMIDINES SUBSTITUES ET UTILISATION DE CES COMPOSES
WO1998011223A1 (fr) 1996-09-11 1998-03-19 Schering Aktiengesellschaft Anticorps monoclonaux diriges contre le domaine extracellulaire de la proteine du recepteur kdr de vegf humain
WO1998010767A2 (fr) 1996-09-13 1998-03-19 Sugen, Inc. Utilisation de derives de la quinazoline pour la fabrication d'un medicament destine au traitement de troubles cutanes hyperproliferatifs
EP0837063A1 (fr) 1996-10-17 1998-04-22 Pfizer Inc. Dérivés de 4-aminoquinazoline
WO1998035958A1 (fr) 1997-02-13 1998-08-20 Novartis Ag Phthalazines a activite inhibitrice de l'angiogenese
WO1999003854A1 (fr) 1997-07-18 1999-01-28 Novartis Ag Modification de la forme cristalline d'un derive n-phenyl-2-pyrimidineamine, procede de preparation et d'utilisation de ce dernier
WO1999017804A1 (fr) 1997-10-03 1999-04-15 Pharmacia & Upjohn S.P.A. Derives polymeres de camptothecines
WO2000009495A1 (fr) 1998-08-11 2000-02-24 Novartis Ag Derives d'isoquinoline possedant une activite d'inhibition de l'angiogenese
WO2000027820A1 (fr) 1998-11-10 2000-05-18 Novartis Ag Derives de n-aryl(thio)anthranilique acide amide, leur preparation et leur utilisation en tant qu'inhibiteurs de la tyrosine kinase du recepteur vegf
WO2000027819A2 (fr) 1998-11-10 2000-05-18 Schering Aktiengesellschaft Amides d'acide anthranilique et leur utilisation comme medicament
WO2000029382A1 (fr) 1998-11-17 2000-05-25 Novartis Ag Caprolactames substitues, compositions pharmaceutiques contenant ces composes et leur utilisation dans le traitement des tumeurs
WO2000037502A2 (fr) 1998-12-22 2000-06-29 Genentech, Inc. Antagonistes du facteur de croissance endotheliale et leurs utilisations
WO2000059509A1 (fr) 1999-03-30 2000-10-12 Novartis Ag Derives de phtalazine pour le traitement des maladies inflammatoires
WO2001055114A1 (fr) 2000-01-27 2001-08-02 Novartis Ag Derives de 2-amino-nicotinamide et leur utilisation comme inhibiteurs de tyrosine kinase du recepteur vegf
WO2001058899A1 (fr) 2000-02-09 2001-08-16 Novartis Ag Derives de pyridine inhibant l'angiogenese et/ou la tyrosine-kinase du recepteur de vegf
WO2004078163A2 (fr) 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Compositions pharmaceutiques a base d'un co-cristal
WO2005037836A2 (fr) 2003-10-15 2005-04-28 Osi Pharmaceuticals, Inc. Imidazopyrazines utilisees comme inhibiteurs de la tyrosine kinase
WO2005097800A1 (fr) 2004-04-02 2005-10-20 Osi Pharmaceuticals, Inc. Inhibiteurs de la proteine kinase heterobicycliques a substitution de noyau bicyclique 6,6
WO2006074991A1 (fr) 2005-01-11 2006-07-20 Neurosearch A/S Nouveaux derives de 2-amino benzimidazole et leur utilisation en tant que modulateurs des canaux a potassium actives par le calcium a faible conductance
WO2007051062A2 (fr) 2005-10-28 2007-05-03 Chemocentryx, Inc. Dihydropyridines substituees et leurs methodes d'utilisation
WO2007084728A2 (fr) * 2006-01-19 2007-07-26 Abbott Laboratories 2-imino-benzimidazoles
WO2008003752A1 (fr) * 2006-07-07 2008-01-10 Neurosearch A/S Dérivés de 2-amino benzimidazole et leur utilisation en tant que modulateurs des canaux de potassium de faible conductance activés par le calcium
US20090163469A1 (en) 2007-12-20 2009-06-25 Novartis Ag Organic Compounds
WO2009080705A2 (fr) 2007-12-20 2009-07-02 Novartis Ag Composés organiques

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE219772T1 (de) * 1998-01-19 2002-07-15 Pfizer 4-(2-keto-1-benzimidazolinyl)piperidin derivate als orl1-rezeptor agoniste

Patent Citations (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4004016A (en) * 1975-08-11 1977-01-18 E. R. Squibb & Sons, Inc. Amino-benzimidazole derivatives
US4100274A (en) 1976-05-11 1978-07-11 Imperial Chemical Industries Limited Polypeptide
EP0039051A2 (fr) 1980-04-24 1981-11-04 Merck & Co. Inc. Derivés des acides hydroxamiques de type des N-bases de Mannich servant comme composés de départ pour la biodisponibilité d'agents anti-inflammatoires non-stéroidiques, procédé de préparation et composition pharmaceutique les contenant
US4636505A (en) 1982-07-23 1987-01-13 Imperial Chemical Industries Plc Amide derivatives
US4659516A (en) 1983-10-12 1987-04-21 Imperial Chemical Industries Plc Steroid derivatives
US5010099A (en) 1989-08-11 1991-04-23 Harbor Branch Oceanographic Institution, Inc. Discodermolide compounds, compositions containing same and method of preparation and use
EP0520722A1 (fr) 1991-06-28 1992-12-30 Zeneca Limited Préparations thérapeutiques contenant des dérivés de quinazoline
EP0566226A1 (fr) 1992-01-20 1993-10-20 Zeneca Limited Dérivés de quinazoline
EP0564409A1 (fr) 1992-04-03 1993-10-06 Ciba-Geigy Ag Dérivés de pyrimidine et procédé pour leur préparation
WO1994010202A1 (fr) 1992-10-28 1994-05-11 Genentech, Inc. Antagonistes du facteur de croissance des cellules endotheliales vasculaires
WO1996010028A1 (fr) 1994-09-29 1996-04-04 Novartis Ag PYRROLO[2,3-d]PYRIMIDINES ET LEUR UTILISATION
WO1996033980A1 (fr) 1995-04-27 1996-10-31 Zeneca Limited Derives de quinazoline
EP0769947A1 (fr) 1995-06-07 1997-05-02 Sugen, Inc. Composes d'indolinone pour le traitement de maladies
WO1997002266A1 (fr) 1995-07-06 1997-01-23 Novartis Ag Pyrrolopyrimidines et leurs procedes de preparation
WO1997007131A1 (fr) 1995-08-17 1997-02-27 Novartis Ag Oligopeptides acyles divers
WO1997008193A1 (fr) 1995-08-17 1997-03-06 Novartis Ag Derives oligopeptidiques acyles presentant une activite inhibant des signaux cellulaires
WO1997028161A1 (fr) 1996-02-01 1997-08-07 Novartis Ag Nouvelles pyrrolo(2,3-d)pyrimidines et leur utilisation en tant qu'inhibiteurs de tyrosine kinase
EP0787722A1 (fr) 1996-02-05 1997-08-06 American Cyanamid Company Dérivés de quinazoline substitués
WO1997030034A1 (fr) 1996-02-14 1997-08-21 Zeneca Limited Derives de la quinazoline servant d'agents antitumoraux
WO1997032879A1 (fr) 1996-03-06 1997-09-12 Novartis Ag 7-ALKYLE-PYRROLO[2,3-d]PYRIMIDINES
WO1997038983A1 (fr) 1996-04-12 1997-10-23 Warner-Lambert Company Inhibiteurs irreversibles de tyrosine kinases
WO1997049688A1 (fr) 1996-06-24 1997-12-31 Pfizer Inc. Derives tricycliques substitues par phenylamino, destines au traitement des maladies hyperproliferatives
WO1997049706A1 (fr) 1996-06-25 1997-12-31 Novartis Ag 7-AMINO-PYRROLO[3,2-d]PYRIMIDINES SUBSTITUES ET UTILISATION DE CES COMPOSES
WO1998011223A1 (fr) 1996-09-11 1998-03-19 Schering Aktiengesellschaft Anticorps monoclonaux diriges contre le domaine extracellulaire de la proteine du recepteur kdr de vegf humain
WO1998010767A2 (fr) 1996-09-13 1998-03-19 Sugen, Inc. Utilisation de derives de la quinazoline pour la fabrication d'un medicament destine au traitement de troubles cutanes hyperproliferatifs
EP0837063A1 (fr) 1996-10-17 1998-04-22 Pfizer Inc. Dérivés de 4-aminoquinazoline
WO1998035958A1 (fr) 1997-02-13 1998-08-20 Novartis Ag Phthalazines a activite inhibitrice de l'angiogenese
WO1999003854A1 (fr) 1997-07-18 1999-01-28 Novartis Ag Modification de la forme cristalline d'un derive n-phenyl-2-pyrimidineamine, procede de preparation et d'utilisation de ce dernier
WO1999017804A1 (fr) 1997-10-03 1999-04-15 Pharmacia & Upjohn S.P.A. Derives polymeres de camptothecines
WO2000009495A1 (fr) 1998-08-11 2000-02-24 Novartis Ag Derives d'isoquinoline possedant une activite d'inhibition de l'angiogenese
WO2000027820A1 (fr) 1998-11-10 2000-05-18 Novartis Ag Derives de n-aryl(thio)anthranilique acide amide, leur preparation et leur utilisation en tant qu'inhibiteurs de la tyrosine kinase du recepteur vegf
WO2000027819A2 (fr) 1998-11-10 2000-05-18 Schering Aktiengesellschaft Amides d'acide anthranilique et leur utilisation comme medicament
WO2000029382A1 (fr) 1998-11-17 2000-05-25 Novartis Ag Caprolactames substitues, compositions pharmaceutiques contenant ces composes et leur utilisation dans le traitement des tumeurs
WO2000037502A2 (fr) 1998-12-22 2000-06-29 Genentech, Inc. Antagonistes du facteur de croissance endotheliale et leurs utilisations
WO2000059509A1 (fr) 1999-03-30 2000-10-12 Novartis Ag Derives de phtalazine pour le traitement des maladies inflammatoires
WO2001055114A1 (fr) 2000-01-27 2001-08-02 Novartis Ag Derives de 2-amino-nicotinamide et leur utilisation comme inhibiteurs de tyrosine kinase du recepteur vegf
WO2001058899A1 (fr) 2000-02-09 2001-08-16 Novartis Ag Derives de pyridine inhibant l'angiogenese et/ou la tyrosine-kinase du recepteur de vegf
WO2004078163A2 (fr) 2003-02-28 2004-09-16 Transform Pharmaceuticals, Inc. Compositions pharmaceutiques a base d'un co-cristal
WO2005037836A2 (fr) 2003-10-15 2005-04-28 Osi Pharmaceuticals, Inc. Imidazopyrazines utilisees comme inhibiteurs de la tyrosine kinase
WO2005097800A1 (fr) 2004-04-02 2005-10-20 Osi Pharmaceuticals, Inc. Inhibiteurs de la proteine kinase heterobicycliques a substitution de noyau bicyclique 6,6
WO2006074991A1 (fr) 2005-01-11 2006-07-20 Neurosearch A/S Nouveaux derives de 2-amino benzimidazole et leur utilisation en tant que modulateurs des canaux a potassium actives par le calcium a faible conductance
WO2007051062A2 (fr) 2005-10-28 2007-05-03 Chemocentryx, Inc. Dihydropyridines substituees et leurs methodes d'utilisation
WO2007084728A2 (fr) * 2006-01-19 2007-07-26 Abbott Laboratories 2-imino-benzimidazoles
WO2008003752A1 (fr) * 2006-07-07 2008-01-10 Neurosearch A/S Dérivés de 2-amino benzimidazole et leur utilisation en tant que modulateurs des canaux de potassium de faible conductance activés par le calcium
US20090163469A1 (en) 2007-12-20 2009-06-25 Novartis Ag Organic Compounds
WO2009080705A2 (fr) 2007-12-20 2009-07-02 Novartis Ag Composés organiques

Non-Patent Citations (20)

* Cited by examiner, † Cited by third party
Title
"Protective Groups in Organic Chemistry", 1973, PLENUM PRESS
"Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY
"Remington's Pharmaceutical Sciences", 1990, MACK PRINTING COMPANY, pages: 1289 - 1329
"Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING COMPANY
"The Practice of Medicinal Chemistry", 2001, ACADEMIC PRESS
BOULAY ET AL., CANCER RES, vol. 68, 2008, pages 3743 - 3751
BUNDGAARD, J. MED. CHEM., 1989, pages 2503
BUNDGAARD: "Design of Prodrugs", 1985, ELSEVIER
F. YUAN ET AL., PROC. NATL. ACAD. SCI. USA, vol. 93, December 1996 (1996-12-01), pages 14765 - 14770
HOUBEN-WEYL: "Methoden der organischen Chemie", vol. 15/1, 1974, GEORG-THIEME-VERLAG
J. MORDENTI ET AL., TOXICOLOGIC PATHOLOGY, vol. 27, no. 1, 1999, pages 14 - 21
LARSSON ET AL., BR. J. CANCER, vol. 92, 2005, pages 2097 - 2101
M. PREWETT ET AL., CANCER RESEARCH, vol. 59, 1999, pages 5209 - 5218
M. S. O'REILLY ET AL., CELL, vol. 79, 1994, pages 315 - 328
M. S. O'REILLY ET AL., CELL, vol. 88, 1997, pages 277 - 285
MELNICK JS ET AL., PROC NATL ACAD SCI USA, vol. 103, 2006, pages 3153 - 3158
O'BRIEN J. ET AL., EUR. J. BIOCHEM., vol. 267, 2000, pages 5421 - 5426
STAHL, WERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2002, WILEY-VCH
THEODORA W. GREENE: "Protective Groups in Organic Synthesis", 1981, JOHN WILEY & SONS
Z. ZHU ET AL., CANCER RES., vol. 58, 1998, pages 3209 - 3214

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014177977A1 (fr) 2013-05-02 2014-11-06 Pfizer Inc. Dérivés d'imidazo-triazine utilisés comme inhibiteurs de la pde10
US11873298B2 (en) 2017-10-24 2024-01-16 Janssen Pharmaceutica Nv Compounds and uses thereof

Also Published As

Publication number Publication date
EP2582681A1 (fr) 2013-04-24
JP2013532149A (ja) 2013-08-15
CN102947275A (zh) 2013-02-27
US20130085161A1 (en) 2013-04-04

Similar Documents

Publication Publication Date Title
KR102354271B1 (ko) 티아디아졸 유사체 및 smn-결핍-관련-상태의 치료 방법
EP2729466B1 (fr) Nouveaux dérivés de pyrrolopyrimidine
JP7337951B2 (ja) 癌を治療するための窒素含有芳香族ヘテロ環アミド誘導体
KR101413392B1 (ko) 단백질 키나제 억제제로서의 화합물 및 조성물
TWI706939B (zh) 新穎二取代１,２,４-三化合物
HUE029617T2 (en) Indazolyl triazole derivatives as IRAK inhibitors
UA71610C2 (uk) Біциклічні гетероцикли та фармацевтична композиція на їх основі
AU2008273426A1 (en) Di(arylamino)aryl compounds
NZ538617A (en) Azaarene derivatives
EA022271B1 (ru) Гетероциклические замещенные соединения арила в качестве ингибиторов hif
HUE035292T2 (en) vegf-r2 inhibitor pyridyl oxindoles and their use in the treatment of disease
JP2008531679A (ja) オキシトシンアンタゴニストとしての１，２，４−トリアゾール誘導体とその使用
EA021464B1 (ru) Производные индол-пиридона, обладающие ингибиторной активностью в отношении киназы 1, содержащая их фармацевтическая композиция и их применение
US9546173B2 (en) Substituted pyrrolo[3,4-d]pyrimidines as kinase inhibitors
EP2582681A1 (fr) Dérivés de 1,3 dihydro-benzoimidazol-2-ylidène-amine à substitution pipéridinyle
EP2582680A1 (fr) Dérivés de 1,3 dihydro-benzoimidazol-2-ylidène-amine à substitution biphényle
WO2019243530A1 (fr) Composés inhibiteurs d'oga
WO2019081691A1 (fr) Nouveaux dérivés d'alcoxyamino permettant de traiter la douleur et des états pathologiques associés à la douleur
JP6314196B2 (ja) 医薬組成物
JP6423877B2 (ja) プロキネチシン受容体調節薬としてのピペラジン誘導体及びアゼピン誘導体
TW201910325A (zh) 吲哚衍生物及其用途

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201180029739.X

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11725116

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2011725116

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2013514720

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 13704380

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE